1. Field of the Invention
The present invention relates to a process for the preparation of primary aromatic carboxamides by reacting aromatic compounds, which contain a leaving group, with carbon monoxide and a primary carboxamide, for example formamide, in the presence of a homogeneous or heterogeneous palladium catalyst and an acylation catalyst at an elevated temperature.
2. Description of the Prior Art
In J. Am. Chem. Soc. 1989, 111, pages 8742 to 8744, Y. Ben-David et al. describe the carbonylation of aryl halides in the presence of a specific Pd(0) phosphine complex, whereby depending on the nucleophile used, for example water, alkanol or secondary amine, arylcarboxylic acids, arylcarboxylates or arylcarboxamides are obtained. If dimethylformamide is used as the solvent during the reaction, it is inert and does not lead to arylcarboxylic acid dimethylamides. Under the conditions of this reaction, the production of primary amides is practically excluded and is also not mentioned.
In Tetrahedron Letters 39 (1998), pages 2835 to 2838, E. Morera et al. describe the preparation of primary aromatic carboxamides, in which an aryl iodide or triflate is carbonylated in the presence of a homogeneous Pd catalyst and hexamethyldisilazane, and afterwards the reaction mixture is worked up hydrolytically. The starting products are expensive and the necessary hydrolytic working up is uneconomical, so that this process is not suitable for use on an industrial scale.
In J. Org. Chem. 1993, 58, pages 7016 to 7021, J. Perry et al. describe the preparation of arylbenzimidazoles by reacting iodine aromatics, 1,2-phenylene and carbon monoxide in the presence of a palladium catalyst and a tertiary nitrogen base in N,N-dimethylacetamide as solvent. It is also mentioned that aromatic N,N-dimethylcarboxamides are produced as a by-product, the formation of which is explained by a decomposition of the solvent.
It has now surprisingly been found that primary aromatic carboxamides are obtained with high selectivity and in a high yield it carbonylation is carried out by starting with aromatic compounds which contain a leaving group, with homogeneous or even heterogeneous Pd catalysts, in the presence of at least stoichiometric amounts of a primary carboxamide, for example formamide, and additionally in the presence of an acylation catalyst. Selectivity and high yields are attained even if N-alkylated carboxamides are used as the solvent.
The subject matter of the invention is a process for the preparation of primary aromatic carboxamides by the carbonylation of an aromatic compound, which contains at least one leaving group, with carbon monoxide, in the presence of a homogeneous or heterogeneous Pd catalyst and at least stoichiometric amounts of an amidation agent at elevated temperatures, which is characterised in that a primary carboxamide or urethane is used as the amidation agent, and the reaction is carried out in the presence of an acylation catalyst.
The aromatic compounds in question may be hydrocarbon aromatics or hetero-aromatics. The hydrocarbon aromatics may contain, for example, 6 to 18 carbon atoms, preferably 6 to 14 carbon atoms, most preferably 6 to 10 carbon atoms. The hetero-aromatics may contain, for example 5 to 17 carbon atoms, preferably 5 to 13 carbon atoms, most preferably 4 to 9 carbon atoms, and at least one hetero atom selected from the group O, S, N and P. The aromatic compounds also include aryl- and heteroaryl-vinyls with a leaving group (especially chlorine or bromine) on a vinyl carbon atom.
Examples of hydrocarbon aromatics are benzene, pentalene, indene, indoline, naphthalene, acenaphthylene, anthracene, phenanthrene, fluorene, triphenylene, pyrene, chrysene, naphthacene, biphenyl, biphenylether, 1,4-diphenylbenzene, vinylbenzene and vinyinaphthalene. Benzene, biphenyl and naphthalene are preferred.
Examples of hetero-aromatics are thiophene, vinylthiophene, benzthiophene, furan, benzofuran, pyran, chromene, pyrrole, vinylpyrrole, imidazole, pyrazole, pyridine, vinylpyridine, bipyridyl, pyrazine, pyrimidine, pyridazine, indole, vinylindole, isoindole, 1H-indazole, quinoline, isoquinoline, phthalazine, quinoxaline, quinazoline, carbazole, acridine, phenanthroline, phenazine, thiazole, isothiazole, phenothiazine, oxazole, isooxazole, phenoxazine, pyrazole, piccoline, and lutidine.
The hydrocarbon aromatics and hetero-aromatics may be unsubstituted or substituted by at least one inert substituent, for example 1 to 3 inert substituents. Examples of substituents are C1-C8-, preferably C1-C4-alkyl, C1-C8-, preferably C1-C4-alkoxy, C1-C8-, preferably C1-C4-halogenalkyl,C1-C8-, preferably C1-C4-hydroxyalkyl, C1-C8-, preferably C1-C4-cyanoalkyl, and xe2x80x94CN.
Examples of alkyl substituents are methyl, ethyl, n- and isopropyl, n-, iso- and tert.-butyl, pentyl, hexyl and octyl. Examples of alkoxy substituents are methoxy, ethoxy, n- and isopropoxy, n-, iso- and tert.-butoxy, pentoxy, hexoxy and octoxy. Examples of halogenalkyl substituents are fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, perfluoroethyl, chloroethyl, n- and iso-chloro- or -fluoropropyl, n-, iso- and tert-chlorobutyl. Examples of hydroxyalkyl substituents are hydroxymethyl, xcex2-hydroxyethyl, n-hydroxypropyl and n-hydroxybutyl. Examples of cyanoalkyl substituents are cyanomethyl, 2-cyanoeth-1-yl and 3-cyanoprop-1-yl.
Leaving groups are known and are described in literature. Examples of leaving groups are, in particular, halides such as chloride, bromide and iodide, as well as the group Rxe2x80x94S(O2)xe2x80x94Oxe2x80x94, wherein R is fluorine, chlorine, halogen-methyl, phenyl, halogen-phenyl, mono-, di- or trimethylphenyl or mono-, di- or tri(halogenmethyl)phenyl. Examples are fluorosulphonyloxy, chlorosulphonyloxy, methylsulphonyloxy, trifluoromethylsulphonyloxy, nonaflate and tosylate. Other known leaving groups are aryl-substituted methoxy groups, such as diphenylmethoxy, di(methylphenyl)methoxy, trityl and tri(methylphenyl)methoxy. Preferred leaving groups are halides, especially chloride and bromide.
In the context of the invention, stoichiometric amounts of amidation agent signifies at least an equimolar amount of amidation agent, based on the aromatic compound containing leaving groups, so that there is at least one equivalent of amidation agent per leaving group. The aromatic compound preferably contains two and most preferably one leaving group, so that in this case at least two, or at least one mol of amidation agent is used per mol of aromatic compound. It may be advantageous to use a surplus of amidation agent, for example up to a molar excess of more. A high excess may be used, especially if the amidation agent serves as the solvent at the same time, for example formamide.
The presence of carbon monoxide can mean that the reaction is carried out with pure carbon monoxide, or with mixtures of carbon monoxide with an inert gas, for example nitrogen or noble gases (helium, neon, argon).
The reaction may be carried out under slightly reduced pressure, at normal pressure or preferably at high pressure. High pressure may mean, for example, up to 100 bar, preferably up to 50 bar. The reaction is most preferably carried out at a pressure of 1 to 20 bar, particularly preferably at a pressure of 1 to 10 bar.
Elevated temperature in the context of the invention can mean a temperature range of 30 to 250xc2x0 C., preferably 50 to 200xc2x0 C., most preferably 80 to 140xc2x0 C.
Pd catalysts are known and have been described in literature many times, see for example J. Tsui in Palladium Reagants and Catalysts, John Wiley and Sons (1995). These are generally Pd(0) complexes with ligands from the group mono- and bidentate, tertiary or ditertiary amines, phosphines and arsines. Phosphines are preferred. The N, P and As atoms of the ligands may be substituted by identical or different hydrocarbon radicals having preferably 1 to 18, most preferably 1 to 12, and especially 1 to 8 carbon atoms. The hydrocarbon radicals may be selected from the group linear and branched C1-C12-alkyl, cycloalkyl with 5 to 7 ring carbon atoms, which is unsubstituted or substituted by C1-C4-alkyl; C6-C10-aryl which is unsubstituted or substituted by C1-C4-alkyl; especially phenyl and alkylphenyls; benzyl which is unsubstituted or substituted by C1-C4-alkyl. Two of the substituents on the N, P and As atoms may also represent an aliphatic hydrocarbon radical which is unsubstituted or substituted by C1-C4-alkyl, and which, together with these hetero atoms, forms a 5- or 6-membered ring; for example two substituents may signify tetramethylene or pentamethylene. With bidentate ligands, two of the N, P and/or As atoms are linked by a linear, bivalent hydrocarbon group, which is unsubstituted or substituted by C1-C4-alkyl, to two to five, preferably two to four carbon atoms, whereby the bivalent hydrocarbon group can be part of a ring or ring system. Suitable bidentate ligands are also those which contain a tertiary amine group and a tertiary phosphine group.
Some examples of ligands are trimethylphosphine, triethylphosphine, tris(t-butyl)phosphine, tricyclohexylphosphine, tri(methylcyclohexyl)phosphine, methyl(tetramethylene)phosphine, t-butyl(pentamethylene)phosphine, triphenylphosphine, tri(methylphenyl)phosphine, 1,2-diphenylphosphine-cyclohexane or -cyclopentane, 2,2xe2x80x2-(diphenylphosphine)biphenyl, 2,2xe2x80x2-(diphenylphosphine)biphenylether, 1,2-bis(diphenylphosphine)ethane, 1,3-bis(diphenylphosphine)propane, 1,4-bis(diphenylphosphine)butane, 3,4-bis(diphenylphosphine)pyrrolidine, 2,2xe2x80x2-(diphenylphosphine)bisnaphthyl (Binap), 1,1xe2x80x2-bis(diphenylphosphin)ferrocene, 1-diphenylphosphine-1xe2x80x2-dicyclohexylphosphine-ferrocen (Josiphos), diphenylphosphine ether (Dpephos), and N-methyl 3,4-diphenylphosphinomethyl-pyrrolidine.
Pd catalysts are generally obtained from Pd(II) or Pd(0) compounds by complexing with ligands. Suitable compounds are, for example, palladium dihalides and diacetate, palladium sulphate, PdCl2[P(C6H5)3]2, Pd2(dibenzylidene-acetone)3 and Pd[P(C6H5)3]4. The catalyst may be produced separately and then used. It is especially advantageous in the process according to the invention to produce the catalyst in situ, whereby a Pd(II) salt which is complexed with ligands is firstly presented or prepared, it required, an excess (for example an equimolar excess) of the ligand is additionally added, the aromatic compound, a formamide, an acylation catalyst and optionally an inert solvent are added. If the reaction is started by applying carbon monoxide and heating the reaction mixture, in the reductive reaction mixture the desired Pd(0) catalyst is formed as a catalytically active element.
As already described, the palladium catalyst can be formed from a heterogeneous catalyst precursor, for example colloidal Pd(0), Pd(0) applied to carrier materials, or Pd(II) compounds applied to carrier materials, for example PdO or Pd(II) salts. Suitable carrier materials are for example inorganic metal oxides, silicates and carbon.
The catalyst may be used in a concentration of 0.001 mol %, to 10 mol %, preferably in a concentration of 0.01 mol % to 5 mol %, most preferably from 0.01 mol % to 3 mol %, based on the aromatic compound.
The carboxamides used according to the invention as amidation agents may be primary carboxamides of mono- or polycarboxylic acids, or urea. They are preferably aliphatic carboxylic acids. The polycarboxylic acids preferably contain 2 to 4, most preferably 2 or 3 carboxyl groups. Suitable carboxamides are at least partially soluble in the reaction medium. The amides may be derived from aliphatic or cycloaliphatic carboxylic acids with for example 1 to 18, preferably 1 to 12 carbon atoms, whereby commercially available, inexpensive carboxylic acids are preferred in particular, since in the process according to the invention the carboxamides serve as amine suppliers for the preparation of other carboxamides. One preferred group is formamide and primary C1-C6-, especially C4-C4-alkylcarboxamides, whereby the alkyl may be linear or branched. Urea and formamide are preferred in particular.
The carboxamides may correspond, for example, preferably to formula I,
R1[C(O)xe2x80x94NH2]xxe2x80x83xe2x80x83(I),
wherein x is 1, and R1 signifies H, NH2, OR2 or linear or branched alkyl with 1 to 6 and preferably 1 to 4 carbon atoms, or wherein x is 2 and R1 signifies a direct bond or linear or branched alkylene with 1 to 6 and preferably 1 to 4 carbon atoms, and R2 is linear or branched alkyl with 1 to 6 and preferably 1 to 4 carbon atoms.
One preferred embodiment of the carboxamides of formula I is the one in which (a) x is equal to 1 and R1 is H, NH2, methyl, ethyl, n- and iso-propyl, n-, iso- and tert.-butyl, and (b) x is equal to 2 and R1 signifies methylene, ethylidene, 2,2-propylidene, ethylene, methylethylene, 1,3-propylene and 1,2-, 1,3- or 1,4-butylidene.
Some preferred examples of primary carboxamides are formamide, acetamide, propionic acid amide, butyric acid amide, urea, oxalic acid diamide and malonic acid diamide.
The acylation catalyst may be used in catalytic or up to stoichiometric amounts or in excess, based on the aromatic compound. The amount may be, for example, 0.01 to 500, preferably 0.1 to 150, most preferably 1 to 100 mol %, based on the aromatic compound.
Acylation catalysts are known per se, whereby in general organic nitriles and especially N-basic compounds with an imine group are primarily used.
The acylation catalysts are, for example, nitrogen bases with an imine group, which have a pKa value of at least 4 and up to 12. The pKa value is preferably 5 to 10.
The acylation catalysts are in particular organic N-basic compounds with an imine group, whereby heterocyclic and heteroaromatic compounds are preferred. Examples are 2H-pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, 3H-indole, 1H-indazole, purine, isoquinoline, quinoline, phthalazine, naphthydrine, quinoxaline, quinazoline, pteridine, acridine, phenanthroline, phenazine, imidazoline, triazine, 2-piccoline, lutidine, benzimidazole, methylimidazole, pyrazole, 4-dimethylaminopyridine, 4-pyrrolidinopyridine, 1,3,5-triazine and 4-methylaminopyridine.
The process according to the invention may be carried out without or in the presence of an inert solvent. Suitable solvents are, for example aliphatic, cycloaliphatic and aromatic hydrocarbons (pentane, hexane, petroleum ether, cyclohexane, methylcyclohexane, benzene, toluene, xylene), aliphatic halogen-hydrocarbons (methylene chloride, chloroform, di- and tetrachloroethane), nitriles (acetonitrile, propionitrile, benzonitrile), ethers (diethylether, dibutylether, tert.-butylmethylether, ethylene glycol dimethylether, ethylene glycol diethylether, diethylene glycol dimethylether, tetrahydrofuran, dioxane, diethylene glycol monomethyl- or monoethylether), ketones (acetone, methyl isobutyl ketone), carboxylates and lactones (ethyl and methyl acetate, valerolactone), N-substituted lactams (N-methylpyrrolidone), carboxamides (dimethylamide, dimethylformamide), acyclic ureas (dimethyl imidazolinum), and sulphoxides and sulphones (dimethyl sulphoxide, dimethyl sulphone, tetramethylene sulphoxide, tetramethylene sulphone).
One preferred embodiment of the process according to the invention consists in the simultaneous use of formamide as the amidation agent and solvent.
The process according to the invention may be carried out for example in such a way that the isolated Pd(0) catalyst is placed in an agitating autoclave, or a Pd compound or a heterogeneous Pd catalyst is placed in the autoclave optionally together with an excess of complexing ligands, and then the acylation catalyst is added. Afterwards, the aromatic compound containing a leaving group is added, and also optionally a solvent, and the autoclave is closed. Prior to the start of the reaction, the autoclave may be flushed with an inert gas, for example nitrogen. Then, carbon monoxide is applied, the reaction mixture is heated for a lengthy period of time and allowed to cool after the reaction, then isolated and the primary aromatic carboxamide obtained is purified by known methods, for example by extraction, crystallisation, distillation and chromatography. It may be advantageous to add water-binding agents to the reaction mixture, for example molecular sieves.
The aromatic carboxamides produced according to the invention are valuable intermediates in the preparation of pharmaceutical and pesticidal compositions, see for example EP-A-0 225 673, EP-A-0 279 633 and EP-A-0 753 508.